Candida albicans is the most common etiological agent of candidiasis, now the fourth leading cause of nosocomial infections carrying high levels of mortality despite currently available therapy. The human host and C. albicans have a long history of association. Consequently, this high degree of co-existence has led to the evolution of layers of defense mechanisms in the host and layers of virulence mechanisms in this opportunistic pathogen. It is clear that mechanisms of host immunity and pathogen virulence intertwine, giving rise to the highly complex nature of host-fungus interactions. However, the interplay between host immunity and fungal virulence has traditionally been ignored in the in the study of C. albicans pathogenesis and most investigations into these topics are overwhelmingly "one-sided". We have constructed a genetically engineered strain of C. albicans (tet-NRG1) that allows "in vivo" modulation of morphology and virulence, and here we propose to use this strain to gain insight into the mechanisms involved in immune defense against systemic infection. The specific aims of this application are: i) to analyze the immune response and characterize protective immune mechanisms during infection with our C. albicans tet-NRG1 strain at different stages of the infectious process, and under conditions leading to colonization (when cells are maintained in the yeast morphology) or active disease (when filamentation is allowed to occur);ii) to investigate the mechanisms of innate and adaptive immunity by which primary infection with this strain protects against a subsequent challenge with a wild type virulent C. albicans strain;and iii) to examine the patterns of expression and role of Toll-like receptors in the innate and adaptive immunity responsible for protection against primary and secondary infections. Relevance to public health: Candida albicans is the main causative agent of candidiasis, the most frequent fungal infection and now the fourth leading cause of infections in US hospitals, with high mortality rates and soaring economic burden. Our long term goal is to understand how the interplay between host immunity and candidal virulence determines the outcome of infection. Results are likely to lead to the development of new immune-based strategies for the prevention and treatment of systemic candidiasis that are urgently needed.